Superficial venous thrombophlebitis (SVT) is a condition of inflammation of vein caused by a thrombus formation in a vein below the skin surface resulting from an injury to vein. It is also caused due to the use of intravenous catheterization or a surgical procedure.
Infusion related superficial venous thrombophlebitis (SVT) is common in hospitalized patients who receive intravenous therapies. This localized thrombophlebitis increases pain and suffering of patients resulting in increased cost of therapy due to frequent change of venous catheter lines as well as treatment of complications of local venous thrombophlebitis. (Arun B and Sharmila V. Prophylactic topical heparin can prevent or postpone intravenous cannula induced superficial thrombophlebitis. Med Hypotheses 2010; 74: 857-858). Superficial venous thrombophlebitis may also complicate varicose veins. According to published literature, the incidence of this complication ranges between 5.6 and 44%. (Katzenschlager R, Ugurluoglu A, Hirsch M. Liposomal heparin-spraygel in comparison with subcutaneous low molecular weight heparin in patients with superficial venous thrombosis. A randomized, controlled, open multicentre study, J Kardiol 2003; 10(9): 375-378)
Heparin is used in the treatment of SVT topically as well as systemically. It belongs to a group of compounds that inhibit blood coagulation and/or the compounds that inhibit platelet aggregation. The topical use of such compounds is more convenient option than the systemic delivery. Apart from the avoidance of further complications due to systemic delivery, locally acting anticoagulants/antithrombotic agents have positive effects on the reduction in the size of thrombus (Clot) and pain/inflammation. Topical heparin formulations are also used for management of varicose veins bruises due to various types of external injuries, inflammable infiltrates and venous ulcers. (Belcaro G, Cesarone M, Dugall M, Feragalli B, Ippolito E, Corsi M et al. Topical formulation of heparin is effective in reducing the symptoms of superficial venous thrombosis: a monocenter, observer-blind, placebo-controlled randomized study. Panminerva Med 2011; 53 (Suppl. 1 to No. 3): 3-11)
Topical formulations of heparin or its pharmaceutically acceptable salts are used for the treatment of thrombophlebitis. These formulations are available in the form of viscous gels, thixotropic sprayable gels, ointments, creams or in the form of liposomal formulations, wherein the drug is incorporated in a Phospholipid bilayer. Higher dose of topical heparin formulations have advantageous therapeutic effects as compared to the lower dose formulations. Despite the use of high concentration of Heparin salt in the formulation inadequate skin penetration of the drug from the known topical formulations leads to sub-par therapeutic effects. This is evident from the longer duration of treatment required to subside the symptoms such as pain and inflammation associated with thrombophlebitis.
The dose of heparin or its variants with different molecular weights such as enoxaparin or Heparin salts such as Heparin sodium, Heparin calcium or heparinoids are mentioned in terms of International Units (IU). Topical formulations of heparin with strength ranging from 50 to 2500 IU/gm are recommended.
Heparin or its salts when used by topical route of administration are intended to provide action below the superficial skin layer. To provide adequate therapeutic benefits it is necessary that these formulations are well absorbed through the skin. Most of the topical formulations applied on the skin in the form of creams/ointments/gels/liposomes do not provide requisite penetration of the drug from the stratum corneum barrier of the skin in requisite concentration and hence, rather than providing desired therapeutic benefit, they merely work as good as a placebo. The formulations containing various ingredients such as thixotropy inducing agents although claim to provide sprayable formulations they result in the formation of a flaky film on the surface of affected area which makes such formulations unacceptable and cosmetically unpleasant for the patient.
Conventional approaches for providing topical formulations of heparin or its salt incorporate the use of lipid-like greasy ingredients or polymers or other ingredients that make them sticky and/or gel-like (highly viscous) in nature and therefore, require sufficient pressure for application of the same on the affected area and/or results in formation of a flaky or gel-like film on the skin surface. Some of the formulations also mandate potent/cytotoxic components such as DMSO which may further irritate the skin of the target area leading to patient discomfort.
All these topical formulations of Heparin or its salt use high proportion of water as the principal carrier without considering the impact of such predominantly aqueous formulations on transdermal penetration of Heparin.
Various approaches have been adopted to provide enhanced penetration of different pharmaceutically active agents especially polar active agents such as the salts of a pharmaceutically active agent. One of them is the incorporation of lipophilic penetration enhancers in the oily phase and the drug in the aqueous phase by way of formulating emulsions/microemulsions.
Further, various emulsifiers/surfactants are employed to dissolve the highly lipophilic component by formation of micelles in a system containing water or by preparing oil in water (o/w) emulsions. However, such emulsion formulations, unless well formulated, are highly unstable in nature and tend to cream due to the coalescence of lipid globules upon storage resulting in non-uniform dose distribution in a formulation. It is also important to control the globule size of the dispersed phase in such a formulation to ensure dose uniformity and stability. These emulsions are available in the form of opaque creams, lotions or translucent formulations.
Another approach is the incorporation of a phospholipid component in the formulation as an essential ingredient which engulfs the drug in solubilized state to form vesicles filled with aqueous solution of the drug, known as liposomes. However, apart from the inherent stability issues, formulation of such system is complex, highly time consuming and non-reproducible.
Further, some to the formulations also suggest the use of predominantly aqueous systems which mandates the use of specific excipients in the form of a polymer or a surfactant or one or more penetration enhancers. None of these focus on arriving at an improved carrier system which in itself is capable of providing optimum transdermal penetration even in absence of the ingredients such as surfactants or use of high proportion of penetration enhancers.
Therefore, there is an unmet need for stable topical formulations capable of providing pharmaceutically acceptable salts of heparin in a therapeutically effective amount that provide enhanced penetration of the drug and at the same time provide excellent patient compliance with pleasant feel on the skin surface as well as reduced untoward effects.
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There is a need for the topical formulations of pharmaceutically acceptable salts of Heparin capable of providing safe, stable, reproducible dosage forms for a requisite amount of drug using optimum amount of water which at the same time provide enhanced transdermal penetration and are administered with ease leading to better patient compliance.